Novel Mechanisms and Therapies in Heart Failure

The central theme of our PPG renewal is to discover novel G protein-coupled receptor (GPCR) signaling pathways that mediate physiologic and pathologic growth of the heart. This well-focused PPG will be led by project leaders who have a long history of collaboration, as demonstrated by numerous co-authored publications and collaborative grants. This history of close collaboration between the project leaders has resulted in thematically integrated projects, ideally suited for a PPG. We propose 3 projects that address unique aspects of GPCR signaling and which will be directed by project leaders that are distinguished scientists in their field. The themes for each of the 3 projects are: Project 1 (Rockman) will determine the molecular and structural basis for stretch mediated -arrestin biased mechanosensitive angiotensin receptor signaling; Project 2 (Koch) will study novel aspects of GRK2 function as they relate to nitroso-redox imbalance i.e., oxidative stress balance in cardiomyocytes and its inter-relationship with NOS, particularly in or at the mitochondria; Project 3 (Stamler) will elucidate the regulation by protein S-nitrosylation of signal transduction through the 2AR as a prototypical GPCR important in cardiovascular function (with particular focus on nitrosylation of -arrestins that aso regulate angiotensin receptor signaling). We also propose two scientific cores that are integral to the success of the program by providing both small animal expertise, where our discoveries at the bench can be tested in vivo, and proteomic resources that will synergistically enhance the projects’ potential to discover new signaling proteins and pathways. We believe this highly synergistic program combines uniquely talented investigators with cutting edge molecular and in vivo animal model methodologies, which will lead to novel discoveries in GPCR signaling and potential new therapeutic avenues in heart failure. Our PPG will now take these concepts a step further by introducing the new idea that bias itself can be regulated at the level of GRK’s and -arrestins through conformational changes in the GPCR and through posttranslational modification of the receptor, GRK and -arrestin.

Using quantitative live-cell fluorescence microscopy (Sorkin lab; U PITT) and molecular modeling (Bahar lab), they investigated the effects of the DAT inhibitor cocaine and its fluorescent analog JHC1-64 on the plasma membrane distribution of wild-type DAT and two DAT mutants. Read more

Core C proposes a new approach, Linear Regression with Validated Association (LRVA) that discovers variants by utilizing the knowledge of known associations, making the variants with weaker signals easier to be identified. They have applied their method to Drug Abuse Disorders data set collected from CEDAR provided to them by Dr. Michael Vanyukov (PI of a FRP), and discovered nearly two dozen novel SNPs associated with drug abuse disorders. Literature search suggests that many of these SNPs reside in genes previously known to be involved with substance abuse. Read more